This Opinion constitutes the Court's findings of facts and conclusions of law pursuant to Federal Rule of Civil Procedure 52.

I. INTRODUCTION

Atelvia® --the osteoporosis drug covered by the challenged patents--purports to solve a problem experienced by patients who used earlier osteoporosis drugs: if the earlier drugs were taken with a meal, the active ingredient was captured by the calcium found in food molecules and was not absorbed into the body.[1] When the medicine failed to enter the bloodstream, patients' bones became susceptible to fractures. Atelvia® addressed this " food effect" by combining the active ingredient risedronate with a calcium-blocking agent, EDTA, thus permitting patients to take the drug with a meal and still receive an effective dose.

It is uncontested that prior art disclosed combinations of the active ingredient and the calcium-blocking agent EDTA

Page 646

to increase absorption. The closest reference--the Brazilian Application-- disclosed two mechanisms to increase absorption: (1) a process called chelation, where EDTA binds to calcium molecules in food and blocks them from capturing the active ingredient; and (2) permeability enhancement, where large doses of EDTA spread the pathways between intestinal cells, allowing more active ingredient to pass from the intestine into the bloodstream.

By binding to calcium ions in food, chelation increases absorption only when a patient has eaten a meal; absorption of the active ingredient is thus similar regardless of whether a patient has eaten or not. On the other hand, permeability enhancement amplifies overall absorption of any intestinal content. Increased intestinal permeability was viewed as harmful because other drugs or bacteria could also more easily pass into the bloodstream.

Atelvia® employs only the first mechanism: it uses EDTA as a chelator to block the calcium in food, but not to enhance overall intestinal permeability. This achieves what the challenged patents call " pharmaceutically effective absorption," a limitation defined as similar absorption whether a patient has eaten or fasted. Fed exposure within about 50% of fasting exposure is expected to be " pharmaceutically effective absorption." Except for the " pharmaceutically effective absorption" limitation, the parties agree that the Brazilian Application contains " all of the elements of the asserted claim[s]." Thus, the main dispute is narrow: in light of the Brazilian Application's disclosure of EDTA's two mechanisms of absorption, whether it was obvious to modify the reference--using only the first disclosed mechanism of chelation and excluding the second disclosed mechanism of enhanced permeability--thus permitting a patient to take her osteoporosis medicine and receive a similar dose regardless of whether she has or has not eaten. In other words, was it obvious to use EDTA only as a calcium blocking agent to defeat the food effect, and would a skilled artisan have had a reasonable expectation of success in so doing?[2]

II. JURISDICTION

This Court has subject matter jurisdiction over this case pursuant to the patent laws of the United States and 28 U.S.C. § § 1331, 1338, 1367, 2201 and 2202. Venue is proper in this District under 28 U.S.C. § § 1391 and 1400(b). This Court has jurisdiction over the parties.

As required by 21 U.S.C. § 355(j)(2)(A)(vii)(IV), Defendant Teva provided Plaintiffs with a " paragraph IV certification," notifying Plaintiffs that they had submitted an Abbreviated New Drug Application (" ANDA" ), No. 20-3217, to FDA seeking approval to manufacture and market generic versions of Atelvia® before the expiration of the '460 and '459 patents. Warner brought this patent infringement action against Teva within the forty-five day statutory period, filing a Complaint against the Defendant. Teva asserted counterclaims, seeking a finding that the challenged patents are invalid. Warner also filed patent infringement actions against the pharmaceutical companies Watson Laboratories, Ranbaxy, and Impax Laboratories, asserting these same patents. The Watson, Ranbaxy, and Impax actions were each resolved by settlement.

In its case against Teva, Warner has dropped all asserted claims of U.S. Patent No. 8,246,989, and all asserted claims of the '459 and '460 patents except for claim 16 of the '459 patent and claim 20 of the '460 patent. Teva has stipulated to infringement of these claims. (Joint Stipulation of Facts ¶ 40). A bench trial was held regarding the validity of claim 16 of the '459 patent and claim 20 of the '460 patent.

b. Technology At Issue

The challenged patents claim an active ingredient called risedronate sodium. This drug is a member of a class called bisphosphonates, which have been used for decades to treat osteoporosis. This active ingredient is combined with an inactive ingredient called disodium EDTA, which chelates--or binds--metal ions in food, blocking them from capturing the active ingredient when a patient has eaten.

1. Bisphosphonates

Bisphosphonates have been used since the 1980s to treat osteoporosis and Paget's disease. (Trial Tr. 1A.100:16-25).[3] These diseases are characterized by a weakening of the bone. In a healthy human body, bone tissue is continually regenerated in an equilibrium of bone growth and bone disintegration. (Tr. 1A.103:14-104:9). Osteoblasts, a type of cell that builds new bone, are balanced by osteoclasts, a type of cell that destroys bone in a process called resorption. ( Id.; Joint Stipulation of Facts ¶ ¶ 84, 85). In patients with osteoporosis, this normal balance is disrupted and bone resorption exceeds bone growth,

Page 648

leading to lower bone mass and a higher chance of fracture. (Tr. 1A.104:1-6).

Bisphosphonates have a strong affinity for the calcium crystals in bone, binding tightly to bone surfaces. (Tr. 1A.104:10-17). When a bone-destroying osteoclast engulfs a bone particle that is attached to a molecule of bisphosphonate, the osteoclast cell becomes less active or is destroyed. ( Id.; PTX 135, at 176).[4] Consequently, bisphosphonates inhibit bone resorption. (DTX 167, at 280). Over time, the administration of bisphosphonates results in less active bone-destroying osteoclasts, less resorption, and more bone tissue. (Tr. 1A.104:15-24). Many pharmaceutical companies have developed species of bisphosphonate for the treatment of osteoporosis. For instance, Warner marketed a 35 mg delayed-release risedronate tablet, called Actonel®, which is the predecessor drug to the Atelvia® drug at issue. Warner held patents covering risedronate and Warner's Actonel® product, which expired on December 10, 2013. Merck developed an alendronate product, marketed as Fosamax® ; and Hoffmann-La Roche developed an ibandronate product, marketed as Boniva® . (Joint Stipulation of Facts ¶ ¶ 42, 44, 57).

2. The " Food Effect"

Drugs that are administered by mouth travel from the mouth to the stomach, and then through the pylorus to the lower gastrointestinal tract--which includes the small and large intestine. (Joint Stipulation of Facts ¶ ¶ 88, 89). Bisphosphonate absorption occurs, to the largest extent, in the small intestine. (PTX 135, at 179). The small intestine consists of the duodenum, jejunum, and ileum. (DTX 234, at 589; Tr. 1A.106:3-6). There, the bisphosphonate passes from the intestines into the bloodstream.

There are two routes of transportation for molecules to pass from the intestine into the bloodstream: passing through the intestinal membrane cells themselves or passing through the spaces between the cells, called the tight junctions. (PTX 90, at 1744; Tr. 1A.107:1-8). Bisphosphonates do not pass through the membrane cells. Instead, they travel between the cells, through the tight junctions. (DTX 273, at 231; PTX 135, at 178-79; Tr. 1A.107:9-18). Once in the bloodstream, the bisphosphonate circulates; some is excreted and some is delivered to the bones, the site of the drug's action. (DTX 208, at 289; Tr. 1A.107:14-18).

Bisphosphonates are not absorbed, and do not pass into the bloodstream, when taken with a meal. This class of drug not only binds to the calcium in bone, it also binds to any stray calcium ions and other metals[5] it encounters in the stomach and intestines after a meal. (PTX 135, at 178; PTX 90, at 1745; Tr. 1A.108:23-109:4). In the gastrointestinal tract, calcium captures bisphosphonate, forming a combined calcium-bisphosphonate complex that is insoluble and is too big to pass through the intestinal tight junctions and into the bloodstream. (DTX 167, at 280, 283). Thus, when an osteoporosis patient simultaneously eats and takes her bisphosphonate, she does not receive the benefit of the medicine because it never reaches the bone. (Tr. 1A.110:21-111:1). This phenomenon is known as the " food effect."

Page 649

Because bisphosphonates interact with food, Warner's predecessor drug Actonel® had to be taken when the patient had fasted, specifically, after an overnight fast and at least 30 minutes before eating or drinking. (Joint Stipulation of Facts ¶ 53).

3. Chelating Agents

The compound disodium EDTA[6] binds to calcium and other divalent cations. This process is called chelation and EDTA is one of the most widely used and strongest chelators of calcium. (Tr. 1A.117:1-8). It tightly sequesters divalent ions, after which the ions cannot interact with other molecules. (Tr. 2A.26:9-27:5).

The bisphosphonate literature had shown that administering EDTA with bisphosphonate increased bisphosphonate absorption. Two mechanisms account for the increase in absorption: (1) chelation, in that EDTA acted as a calcium blocker; and (2) permeability enhancement, in that EDTA directly increased the permeability of the intestines. ( See DTX 167, at 283; PTX 90, at 1745).

The first mechanism, calcium chelation, operates by blocking calcium from capturing the bisphosphonate active ingredient via competitive inhibition. ( See DTX 167, at 283; PTX 90, at 1745). The active ingredient and the chelating agent both compete for the same pool of stray calcium. By introducing enough chelating agent, stray calcium is more likely to capture the chelating agent than the active ingredient. (Tr. 2B.40:1-2). Like a decoy, chelating agents block calcium ions from capturing the bisphosphonate, while the bisphosphonate remains free to enter the bloodstream without interference.

The second mechanism, increasing intestinal permeability, works by widening the pathway between the tight junctions of intestinal cells--by which bisphosphonate travels from the intestine into the bloodstream--permitting more bisphosphonate to be absorbed. (DTX 273, at 232; DTX 167, at 283; PTX 90, at 1745). The tight junctions between cells have molecules of calcium embedded in the channels. EDTA binds to these molecules, making the spaces between cells wider, and increasing permeability for many particles. (DTX 167, at 283). Thus, larger molecules like bisphosphonates pass more easily into the bloodstream. (PTX 90, at 1745; PTX 135, at 179). But spreading the tight junctions creates a risk that bacterial fragments and increased levels of coadministered drugs will pass through these wider pathways to the bloodstream. (PTX 175, at 1249). Consequently, unduly spreading the tight junctions was viewed as undesirable. (DTX 167, at 280; PTX 90, at 1745; PTX 135, at 185).

c. The Challenged Patents

Both the '459 and '460 patents share a provisional application filed on May 24, 2004. The utility application that issued as the '459 patent was filed on April 15, 2005. The utility application that issued as the '460 patent was filed on November 23, 2005 and is a continuation-in-part of the application that issued as the '459 patent. The '459 patent, entitled " Dosage Forms of Bisphosphonates," and the '460 patent, entitled " Dosage Forms of Risedronate," both issued on January 12, 2010. The patentee disclaimed the terminal part of the '460 patent beyond the expiration of the '459 patent, and both are scheduled to expire on January 9, 2028. (Joint Stipulation of Facts ¶ ¶ 34, 38). The inventors are

Page 650

listed as Richard Dansereau and David Burgio. Claim 16 of the '459 patent, like claim 20 of the '460 patent, comprises one independent claim and several additional dependent claims. Claim 16 of the '459 patent is reproduced below:

8. An oral dosage form having pharmaceutical effective absorption comprising;

(a) from about 1 mg to about 500 mg of risedronate sodium;

(b) from about 75 mg to about 250 mg of disodium EDTA; and

(c) an enteric coating which provides for release of the risedronate sodium and the disodium EDTA in the lower gastrointestinal tract of a mammal.

13. The oral dosage fomi of claim 8 comprising from about 10 mg to about 50 mg of risedronate sodium.

14. The oral dosage form of claim 13 comprising about 100 mg of the disodium EDTA.

15. The oral dosage form of claim 14 comprising about 35 mg of risedronate sodium.

16. The oral dosage form of claim 15 wherein the enteric coating is a methacrylic acid copolymer.

8. An oral dosage form having pharmaceutically effective absorption comprising;

(a) from about 1 mg to about 250 mg risedronate sodium;

(b) from about 25 mg to about 500 mg of disodium EDTA; and

(c) an enteric coating which provides for immediate release of the risedronate sodium and the di sodium EDTA in the small intestine of a mammal.

15. The oral dosage form of claim 8 comprising from about 15 mg to about 55 mg of the risedronate sodium.

16. The oral dosage form of claim 15 comprising from about 75 mg to about 250 mg of the disodium EDTA.

17. The oral dosage form of claim 16 comprising about 35 mg of the risedronate sodium.

19. The oral dosage form of claim 17 comprising about 100 mg of the disodium EDTA.

20. The oral dosage form of claim 19 wherein the enteric coating is a methacrylic acid copolymer.

(
DTX 3, '460 patent, col. 24, ll. 47-55, col. 25, ll. 8-20).

As shown above, claim 16 of the '459 patent and claim 20 of the '460 patent are both limited to an oral dosage form with 35 mg of risedronate sodium, 100 mg of disodium EDTA, and a methacrylic acid copolymer enteric coating. Claim 16 of the '459 patent differs from claim 20 of the '460 patent in the location of release of the formulation: claim 16 requires " release . . . in the lower gastrointestinal tract," whereas claim 20 requires " release . . . in the small intestine." The small intestine is part of the lower gastrointestinal tract. (Joint Stipulation of Fact ¶ 89). Claim 20 of the '460 patent also adds the limitation " immediate release," which means " dissolution of the core tablet in less than 60 minutes, when measured by standard USP definitions." (DTX 3, '460 patent, col. 4, ll. 13-16).

One feature of the claimed invention is the addition of the limitation in both claims called " pharmaceutically effective absorption," which is defined in both the '459 and '460 patents as:

an amount of a chelating compound high enough to significantly bind the metal ions and minerals in food but low enough not to significantly alter absorption of the bisphosphonate[7] as compared to absorption in the fasted state. That is, absorption is similar with or without food. Given the high variability of bisphosphonate absorption, fed exposure within about 50% of fasting exposure is

The patent applications that issued as the '459 and '460 patents originally did not contain the term " pharmaceutically effective absorption." (PTX 3, at 1138). After the PTO examiner rejected the claims as unpatentable--because earlier references disclosed bisphosphonates combined with EDTA to increase absorption--the patentee amended every claim to add the limitation " pharmaceutically effective absorption." (PTX 3, at 636-38, 1138; PTX 5, at 542-544, 648). The examiner allowed the claims after that amendment. The concept is to permit the patient to take the drug either with or without food; however, FDA has approved Atelvia® only to be taken with food.

IV. THE TRIAL

At trial, the evidence centered upon whether the asserted claims of the '459 and '460 patents are invalid due to anticipation or obviousness.

a. Anticipation

" A patent is invalid for anticipation under 35 U.S.C. § 102 if a single prior art reference discloses each and every limitation of the claimed invention." Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 958 (Fed. Cir. 2014). In order to anticipate, the prior art reference must contain " each of the limitations of the claim." Scaltech Inc. v. Retec/Tetra, LLC, 178 F.3d 1378, 1383 (Fed. Cir. 1999). " Claimed subject matter is 'anticipated' when it is not new; that is, when it was previously known. Invalidation on this ground requires that every element and limitation of the claim was previously described in a single prior art reference, either expressly or inherently, so as to place a person of ordinary skill in possession of the invention." Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1082 (Fed. Cir. 2008). " [T]he dispositive question regarding anticipation is whether one skilled in the art would reasonably understand or infer from a prior art reference that every claim element is disclosed in that reference." AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1055 (Fed. Cir. 2010) (quoting In re Baxter Travenol Labs., 952 F.2d 388, 390 (Fed. Cir. 1991)) (internal quotations and alterations omitted). " [T]he party asserting invalidity due to anticipation must prove anticipation, a question of fact, by clear and convincing evidence." Orion IP, LLC v. Hyundai Motor Am., 605 F.3d 967, 975 (Fed. Cir. 2010).

" [A] single prior art reference may anticipate without disclosing a feature of the claimed invention if such feature is necessarily present, or inherent, in that reference." Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 958 (Fed. Cir. 2014). " [I]nherency operates to anticipate entire inventions as well as single limitations within an invention." Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1380 (Fed. Cir. 2003). Recognition of an inherent limitation in the prior art by a person of ordinary skill in the art is not required to establish inherent anticipation. Id. at 1377. An inherent limitation is one that is necessarily present and not one that may be established by " probabilities or possibilities." See Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1268-69 (Fed. Cir. 1991). That is, " [t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Id.

1. The Brazilian Application

Teva introduced evidence that Brazilian Patent Application, ...

Our website includes the first part of the main text of the court's opinion.
To read the entire case, you must purchase the decision for download. With purchase,
you also receive any available docket numbers, case citations or footnotes, dissents
and concurrences that accompany the decision.
Docket numbers and/or citations allow you to research a case further or to use a case in a
legal proceeding. Footnotes (if any) include details of the court's decision. If the document contains a simple affirmation or denial without discussion,
there may not be additional text.

Buy This Entire Record For
$7.95

Download the entire decision to receive the complete text, official citation,
docket number, dissents and concurrences, and footnotes for this case.